Dental resorptive lesions have become one of the most common dental diseases in cats and are occurring with increasing frequency in other species, including humans. Dental resorptive lesions are also known by a variety of other names including odontoclastic resorptive lesions, feline neck lesions, cervical line lesions, chronic subgingival tooth erosions, feline external resorptive lesions, and/or subgingival resorptive lesions. This disease is characterized by cavitating lesions produced by osteoclastic (odontoclastic) resorption originating subgingivally and progressively eroding through the enamel/cementum and dentin layers into the pulpal tissues of the tooth. Odontoclasts are large multinucleated cells of up to about 400 nm in diameter and appear to be derived from the same lineage as osteoclasts, which are the cells responsible for bone resorption. The odontoclasts progressively attack apparently healthy tooth substance, producing large painful tooth lesions, ultimately resulting in tooth breakage with retention of root fragments in the gum.
Observation of dental resorptive lesions during routine examination of cats can be difficult because relatively little erosion of the cementum and enamel may be evident at the buccal surface. However, the lesion is apparent when examined radiographically. Although the lesion may not be obvious, it is commonly accompanied by signs of pain. Other clinical' signs include anorexia, concurrent gingivitis, and excessive salivation. See Elizabeth M. Lund, et al., Prevalence and risk factors for odontoclastic resorptive lesions in cats, JAVMA, Vol. 212, No. 3, pp. 392-95 (Feb. 1, 1998), which is incorporated by reference herein in its entirety.
The primary cause of dental resorptive lesions is not definitively known. Possible causes include oral inflammation, plaque or periodontal disease, systemic disease conditions, dietary factors, breed predisposition, and defects and diseases in the tissues of the tooth or periodontium. Of the studies done on feline dental resorptive lesions, the prevalence of the lesions consistently increases with age. See van Wessum, et al., Feline Dental Resorptive Lesions, Veterinary Clinics of North America. Small Animal Practice, Vol. 22, No. 6, pp. 1405-16 (November 1992), which is incorporated by reference herein in its entirety.
Dental resorptive lesions are distinguishable from other dental diseases, such as periodontal disease, dental caries and alveolar bone loss. Periodontal disease and dental caries are caused by aggressive bacterial or microbial build Up due to poor oral hygiene, malocclusion, tartar build up, food impaction and faulty dental restorations. See Riviere et al., Infection and Immunity, 59(10), 3377-80 (1991), Reddy et al., J Periodontol, 211-217 (March 1995), and Weinreb et al., J. Periodont Res, 29, 35-40 (1994), which are all incorporated by reference herein in their entirety. In periodontal disease, inflammation of the gum around the tooth results in leaching of the alveolar bone causing the teeth to become loose and to eventually fall out. In contrast, dental resorptive lesions can occur in the absence of periodontal disease and are caused by odontoclastic attack on the tooth surface itself, as opposed to the surrounding bone.
Currently, there is no effective treatment for dental resorptive lesions. Often, the affected teeth break off, thus creating the potential for root sequestrum formation and subsequent infection. Typically, affected teeth must be extracted because attempts to save the tooth by drilling out the lesion and filling it with restorative materials are ineffective. Approximately 90% of the repair attempts fall out within two years because of ongoing resorption. In addition, new lesions often develop in other teeth within the mouth of an affected individual. See Ayako Okuda, et al., Challenges in Treatment of External Odontoclastic Resorptive Lesions in Cats, Compendium on Continuing Education for the Practicing Veterinarian, Vol. 17, No. 12, pp. 1461-69 (December 1995), which is incorporated by reference herein in its entirety.
Even though dental resorptive lesions are currently observed primarily in cats, there is the potential for the spread of this disease to other mammalian species, including man. For example, before the 1950s, the presence of feline dental resorptive lesions was extremely rare. However, recent studies have calculated prevalence rates of 28.5% to 57% in the last ten years. See van Wessum, et al., Feline Dental Resorptive Lesions, Veterinary Clinics of North America: Small Animal Practice, Vol. 22, No. 6, pp. 1405 (November 1992). Therefore, there is a need to treat and/or reduce the risk of the condition and its spread.
Bisphosphonates are known in the art to bond to hydroxyapatite in bone and to inhibit the bone resorptive activity of osteoclasts. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 3rd Edition, Parthenon Publishing (1997), which is incorporated by reference herein in its entirety. For example, bisphosphonates are known to be useful in the treatment of such diseases as osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation. Even though bisphosphonates have been used to treat the above-mentioned diseases, they have not been used to treat dental resorptive lesions.
It is surprisingly been found in the present invention that bisphosphonates are effective for inhibiting, i.e. treating and reducing the risk of contracting, dental resorptive lesions. Without being limited by theory, it is believed that new tooth substance is formed by odontoblasts to heal the lesions. Thus, administration of a bisphosphonate can eliminate the need for tooth extraction and its associated complications.
It is also surprisingly found in the present invention that a therapeutically effective amount of a bisphosphonate can be selectively delivered to the subgingival tooth surface and alveoli dentales such that at about 24 hours after administration the resulting average concentration of the bisphosphonate at the subgingival tooth surface and alveoli dentales is at least about two times greater than the average concentration in the skeleton, for example at the diaphysis of the femur.
Because it is estimated that greater than about 25% of cats visiting a veterinarian for any reason have dental resorptive lesions, what is desired in the art is a therapy to optimally inhibit the progression of clinically detectable, active dental resorptive lesions and to reduce the risk of the development of new lesions within the mouth of the affected individual. Also desired is a therapy to eliminate the need for tooth extraction and to alleviate the pain associated with dental resorptive lesions. It is desired that these therapeutics be used to both control the disease in cats and to reduce the risk of the spread of dental resorptive lesions to other species, including humans.
It is an object of the present invention to provide a method for inhibiting dental resorptive lesions in a mammal by administering a bisphosphonate or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a method for treating or reducing the risk of contracting dental resorptive lesions in a mammal by administering a bisphosphonate or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a method for inhibiting dental resorptive lesions in a cat by administering a bisphosphonate or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a method of alleviating the pain associated with dental resorptive lesions in a mammal by administering a bisphosphonate or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a method of reducing the risk of tooth loss associated with dental resorptive lesions in a mammal by administering a bisphosphonate or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to selectively deliver a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof to the subgingival tooth surface and alveoli dentales.
These and other objects will become readily apparent from the detailed description which follows.